This application's broad, long term objective is to learn how to change the trajectory of a chronic wound into that of a normal healing wound. As burn doctors, we see the devastation of chronic wounds on a daily basis. The longer a patient's wound takes to heal, the more time that needs to be spent in the hospital receiving care. Furthermore, the longer the wound takes to heal, because of prolonged inflammation, the worse the ultimate cosmetic and functional outcome. We have found that inflammatory mediators cause increased expression of matrix metalloproteinase 9 (MMP-9). We also find that MMP-9 is pathologically present and activated in chronic wounds. Our hypothesis is that this over-activity of MMP-9 is the reason for the pathogenesis of chronic wounds. The corollary to this is that decreasing the activity of this proteinase may improve clinical wound healing. The first specific aim of this project is to confirm our hypothesis that increased expression of MMP-9 slows wound healing. Once a chronic wound has been created in the presence of super-normal levels of MMP-9, our second specific aim of the project seeks to reverse the effects of MMP-9 using known inhibitors. The experimental design of this project uses a chimeric construct. We will take human skin that has been transfected to over-express human MMP-9 and graft it on a murine host. Once the graft takes to the native wound bed, the grafted human construct will be wounded and compared to that of normal mouse wounds as well as human graft on a murine host that has not been transfected to over-express MMP-9. The reason for this mixed model is because there is evidence that murine MMP-9 may not have the same interactions as human MMP-9. Using a small mammalian host such as the mouse, instead of a human clinical trial, also allows us to increase the power of this experiment in a short amount of time. If we can use an inhibitor to stop the effects of activated MMP-9 in a wound and change the trajectory of chronic wound healing to that of normal, the implications for public health would be tremendous. First, individual patients would require less intensive care for shorter periods of time. Wound care facilities would be able to run more cost effectively and efficiently. Additionally, under the constant threat of disaster, more efficient burn care would prepare our country's burn facilities for calamity. [unreadable] [unreadable] [unreadable]